In the medical, dental, pharmaceutical and veterinary arts there is a need for compositions having highly reproducible characteristics selected from one or more of the following: malleability (from a viscous “oily” liquid or gel to a solid “waxy” material), biocompatibility, low toxicity, the ability to be excreted or otherwise eliminated by the patient, easy and inexpensive to manufacture, and being readily altered to a variety of viscosities and hardnesses. It will be understood that, unless specifically mentioned otherwise, by “oil” or “wax” is meant the physical appearance and handling characteristics of the material rather than a strict chemical definition of the composition.
Thus, nontoxic, resorbable materials that are flowable and/or malleable are highly desirable for a wide range of medical and surgical applications. These materials may be used for a large variety of purpose, including, without limitation, as a hemostat in stopping bleeding tissue and bone wounds; as carrier or matrix for bioactive or inert particles and drugs by a variety of modes of administration, for example orally, or as applied directly to bone or other tissues during surgery to promote healing; as a barrier to prevent adjacent tissue surfaces from sticking together, or to prevent the movement of fluids away from or into tissues; as a lubricant to facilitate the insertion or positioning of devices such as catheters or other implantable devices, as an adhesive putty to keep devices and materials in position during a procedure, and as resorbable coating materials for implants and medical devices.
For example, such a material may be useful in surgery as a bone wax or bone hemostatic composition. Traditionally, bone waxes are made from beeswax mixed with a softening agent such as paraffin to mechanically stem blood flow from bone bleeding; the bone wax is usually smeared across the bleeding edge of the bone, blocking the holes and causing immediate bone hemostasis through a tamponade effect.
However, there are a number of adverse effects inherent in traditional bone wax compositions. Paraffin-based bone wax is not absorbed by the body and thus remains are the site of application indefinitely. Furthermore, traditional paraffin-based bone wax inhibits new bone osteogenesis and acts as a physical barrier preventing bone union, even after it is removed from the site following surgery. Its use is therefore not indicated if bone growth or fusion is desired following surgery.
Substitutes for bone wax have been suggested as an attempt to circumvent these disadvantages; these suggested substitutes include, without limitation, hydrogels, gelatin paste, collagen, fibrin-collagen paste, and bioerodible polyorthoester, among others.
Hydrogels are generally well suited for use in contact with body tissues, having good biocompatibility, low toxicity, and solubility. However, the physical and mechanical properties of hydrogels are generally less than optimal for applications that require even small amounts of manipulation during their use. Crosslinked hydrogels are more elastic than non-crosslinked hydrogels but are not malleable because their gel structure is chemically bonded. Once cured, crosslinked hydrogels are substantially incapable of being molded or manipulated. Exposure to a force beyond the elastic limit of the hydrogel will result in fracture of the gel rather than plastic deformation.
Non-crosslinked hydrogels are formed by hydrophobic or electrostatic interactions. Since the bonding is reversible, such gels may exhibit malleable or flowable properties. In general, these types of materials are a soft gel with low elasticity and resiliency due to the weakness of the bonding force, and they are substantially incapable of being molded. In addition, the stability of certain drugs and bioactive compounds may be compromised in the presence of water. This further limits the applications of hydrogel based carriers.
Petroleum jelly and paraffin wax derived from petroleum, or from plant or animal origin, have suitable mechanical and physical properties for use as malleable, putty-like matrices, coatings, implants, lubricants and barriers. Depending upon the molecular architecture and average molecular weight, the material properties can range from soft flowable gel, gum, malleable soft wax, brittle hard wax, to soft plastics. Unfortunately, these substances are hydrophobic, insoluble in water and, as stated above, cannot be resorbed, metabolized or otherwise removed by the body. In the long run, this type of material may cause inflammation and interfere with wound healing.
Mixtures of hard wax materials, such as beeswax and carnauba wax which are esters of long chain alkanes, have been utilized as bone hemostatic agents. Bleeding from bone cannot be stopped by the same techniques used for soft tissues, such as by applying hemostatic clamps or electrocautery as bone is a rigid structure with a rich blood supply that circulates through a system of canals within the hard mineralized matrix, and extensive network of vessels within the bone marrow. A beeswax formulation applied to the cut surface stops the bleeding very effectively by adhering to the bone and physically occluding the open blood vessels. However, the beeswax remains at the application site long after the surgery, and may cause inflammation, granuloma formation, and interferes with bone healing. As a foreign body, the residual wax may also become a focus of persistent bacterial infection.
It is one object of the invention to provide an alternative to wax- and grease-based materials and methods their preparation for use in medical, dental, pharmaceutical, veterinary, and surgical applications that overcomes the known deficiencies of existing materials.
Porous implant materials are useful for the repair, augmentation and/or reconstruction of the bony skeleton including cartilage. Tissue ingrowth occurs in implants with interconnecting pores, for example, pores of 60 microns or greater average diameter. Porous implants may be made by sintering small particles or beads of a fusible material such as polyethylene or metal. An alternative way to make a porous material is to blend pore forming agents into a molten substrate, which is then cooled. The pore forming agents may then be removed to produce a porous structure.
The surface of highly porous implants is rough, abrasive and exhibits a high coefficient of friction when in contact with tissues. It can therefore be difficult to move porous implants into position during surgery. Moreover, the implant surface tends to collect debris such as fat and cellular material which can later become necrotic and harbor infection. By filling and covering the pores with a resorbable, biocompatible material, the surface roughness can be reduced without compromising the porosity of the material. Therefore, another object of this invention is to provide a porous implant in which the pores are filled or covered with a resorbable substance that is water-soluble and becomes lubricious when wet, resulting in an implant with a smooth surface, without cavities in which debris can become trapped, and with a lubricating layer which helps the surgeon to slide the implant through tissue planes during placement.
Both porous and non-porous granular devices (such as implants) may be used as a scaffold for tissue ingrowth after implantation into a surgical created defect site. The devices can be made from a broad range of natural and synthetic implantable substances, including particles comprised of, but not limited to, native autogenous bone or cartilage, bone or cartilage from cadavers, collagen, hydroxyapatite, bioactive glass, polymethylmethacrylate (PMMA), polytetrafluoroethylene (PTFE), polyethylene, and dimethylpolysiloxane. The performance of particulate (such as porous) implants is markedly improved by the addition of a matrix to temporarily bind the particles together, and to form putty that serves to improve the handling characteristics and to act as a delivery system. Thus, another object of the present invention is to provide a binder or a matrix for particulate implant materials to improve their handling performance.
Collagen, in the form of gelatin solution has been used as a medium for injectable compositions. For example, ARTEPLAST® from Rofil Medical International is an injectable material comprised of microspheres of poly-methylmethacrylate (PMMA) suspended in a gelatin solution, and ARTE-COLL® a product currently available in Europe and Canada, is comprised of smooth PMMA spheres, at a concentration of 25% PMMA/75% collagen by weight with 0.3% lidocaine suspended in bovine collagen. Following implantation, the gelatin is resorbed and replaced by native collagen. However, bovine collagen carries the risk of an immunogenic reaction by the recipient patient, and a potential risk of disease transmission (such as bovine spongiform encephalopathy) from infected bovine, and is not a desirable matrix for allograft bone.
U.S. Pat. No. 5,073,373 discloses the use of glycerol as a matrix for demineralized allograft bone in the form of a gel. For example, GRAFTON® from Osteotech is a simple mixture of glycerol and lyophilized, demineralized bone powder. GRAFTON® works well to allow the surgeon to place the allograft bone at the site. But glycerol is very soluble in blood, and has very low viscosity at body temperature. This causes the allograft bone particles in a glycerol matrix to flow away from the site almost immediately after placement, preventing the proper retention of the allograft bone within the defect site. Moreover, glycerol is toxic and irritating to the surrounding tissues.
U.S. Pat. No. 4,191,747 discloses a bone defect treatment with fat free, denatured bone meal powder. The bone meal is mixed with a polysaccharide in a solution of saline and applied to the bone defect site. U.S. Pat. No. 5,290,558 discloses a flowable, demineralized bone powder composition using an osteogenic bone powder mixed with a low molecular weight polyhydroxy compound from 2 carbons to about 18 carbons in chain length including sugars of different molecular architecture such as monosaccharides, disaccharides, water-dispersible oligosaccharides, and polysaccharides.
U.S. Pat. No. 5,356,629 discloses methods of making a bone cement to fill defects in bone by mixing biocompatible particles, such as PMMA coated with polyhydroxyethylmethacrylate in a biopolymer matrix (e.g., hyaluronic acid) to obtain a moldable semisolid mass. The biocompatible particles can be derived from xenograft bone, homologous bone, autogenous bone, as well as other synthetic substances. The bioactive substance can also be an osteogenic agent such as demineralized bone powder, in addition to morselized cancellous bone, aspirated bone marrow, and other autogenous bone sources.
Poloxamer-based thermo reversible hydrogels are being developed for use as a drug delivery system. The drug-containing Poloxamer solution is liquid at less than 10° C. After administered to the desired location in the body, the drug-containing solution forms a hydrogel as it warms to 37° C. The solidified gel remains at the site, slowly releasing the drug by diffusion and/or gradual dissolution of the gel matrix.
U.S. Pat. No. 6,281,195 discloses a Poloxamer hydrogel matrix for the delivery of osteogenic proteins. In particular, Poloxamer 407 (PLURONIC® F127) is used in the form of a hydrogel. Overall, the hydrogel based system including Poloxamer hydrogel, hyaluronic hydrogel, and polysaccharide hydrogel all exhibit high hydrophilicity, low adhesion to tissue, and low binding capacity for hydrophobic drugs, thus significantly limiting their applications.
U.S. Pat. Nos. 7,553,913, 7,829,616, 8,124,687 and International Patent Application PCT/US2004/004174 teach the use of alloys of alkylene oxide block copolymers and random alkylene oxide copolymers for medical applications. Random alkylene oxide copolymers, such as PLURACOL® V10 from BASF, are highly hydrophilic. Thus, the alkylene oxide copolymer and the random alkylene oxide copolymers have overall hydrophilic properties. Compositions prepared according this invention tends to exhibit faster material solubility, and low binding capacity for hydrophobic medicinal ingredients.
U.S. Patent Publication No. 2009/0286886 teaches resorbable polymer compositions comprised of a poly(alkylene)-poly(ethylene glycol) copolymer and a poly(alkylene glycol) polymer or copolymer for use in medicine, dentistry and surgery. Poly(alkylene)-poly(ethylene glycol) copolymers and their properties are relatively unknown and unproven for use in the medical implant field.
Reverse phase Poloxamer hydrogel, Poloxamer 407 (PLURONIC® F127) has been reported as anti-adhesion barrier for preventing tissue adhesions after reproductive surgery. See Steinleitner A. et al., Poloxamer 407 As An Intraperitoneal Barrier Material For The Prevention Of Postsurgical Adhesion Formation And Reformation In Rodent Models For Reproductive Surgery OBSTET GYNECOL. 77(1):48-52 (January 1991). Various crosslinked hyaluronic acid, or hyaluronic acid-based materials have also been disclosed as anti-adhesion barriers as summarized in U.S. Patent Publication No. 2004/0013714. Overall, the hydrogel based anti-adhesion barriers exhibit low adhesion to tissue due to high hydrophilicity and high water content. The reverse phase Poloxamer hydrogel has no covalent cross-linking and dissolves too quickly into solution, providing insufficient anti-adhesion protection, while the crosslinked hydrogels requires costly synthesis for the preparation and purification of purified crosslinked hydrogel, and the biocompatibility of the purified product is not fully characterized.
Thus, another object of this embodiment of the invention is to provide a biocompatible and substantial anhydrous jelly-like material that are sticky, less water soluble, and is economical to manufacture for use as anti-adhesion barrier.
Copolymers of oxyethylene and oxypropylene have been proposed as materials to be used as a substitute for bone wax. See e.g., Provisional U.S. Patent Application Ser. No. 61/162,347. Examples of such copolymers include Poloxamers (such as surfactants sold under the name PLURONIC®), meroxapols (such as surfactants sold under the name PLURONIC® R), polyoxamines (such as surfactants sold under the name TETRONIC®), and the PLURACOL® surfactants.
Levy et al. (U.S. Patent Publication 2003/0095945 and provisional U.S. Patent Application No. 60/162,347) discloses methods and compositions for bone hemostasis comprising a sterile copolymer comprises a mixture of PLURONIC® polyoxyethylene-polyoxypropylene-polyoxyethylene triblock copolymers for use as a bone hemostasis agent. The application of alkylene oxide block copolymers over the bleeding sites of the bone for hemostasis was described. Claimed advantages over prior art methods include the finding that bone growth was not inhibited, and the water-soluble composition was resorbed and excreted. The preferred material described is a 9:1 blend by weight of two block copolymers: Poloxamer 235 (PLURONIC® P85) and Poloxamer 238 (PLURONIC® F88).
However, the material prepared according to Levy et al. is suboptimal in malleability for use as bone wax. In addition, after the copolymers were made molten, mixed and dissolved at 80° C., the compositions are plunged into liquid N2 (boiling point −196° C. and freezing point −210° C.) to avoid such crystallization from occurring. The use of liquid N2 to snap cool the material causes significant condensation around the working environment, and its use is hazardous and impractical for application in the production of implantable devices due, for example, to possible splashing and spattering of the liquid N2. The formulations of bone hemostasis agents in the prior art lack one or more of the following attributes: biocompatibility, superior handling characteristics, and easy manufacture and storage as disclosed subsequently by some of the same inventors in Int'l Patent Application PCT/US2004/004174.
Wellisz et al., (U.S. Pat. No. 7,553,913 and Patent Publications No. 2009/0238758, 2006/0100370 and 2006/0140904), based on a later application by some of the same inventors of the '945 publication, discusses compositions comprising a) a random copolymer of a polyethylene oxide and other alkylene oxides and b) a non-random polymer comprising one or more poly(alkylene oxide), such as homopolymers and/or block co-polymers. As disclosed in these publications, polymer blends were formulated at 80° C. and the molten polymer blends were molded by casting in small molds and rapidly cooling the molds and composition at 4° C. until fully set (less than 5 minutes).
Fisher et al., (U.S. Patent Publication No. 20090286886) discusses resorbable polymer compositions comprised of a poly(alkylene)-poly(ethylene glycol) copolymer and a poly(alkylene glycol) polymer or copolymer for use in medicine, dentistry and surgery.
None of the compositions disclosed herein possesses the unexpected properties of the present invention, which combines low toxicity, biocompatibility, superior bone hemostatic activity, and controlled dissolution with further characteristics including broader utility, substantially enhanced malleability, adhesion, cohesion, and batch-to-batch uniformity compared to prior art compositions.
In another embodiment it is yet another object of this invention to provide a nonhydrogel polymer matrix for certain materials used in medicine, dentistry, and surgery, including, without limitation, bone particles, bioactive agents (including, without limitation, glasses) and drug components which provides a superior combination of adhesive and cohesive properties, ease of handling, optimal retention time at the site of application, minimal swelling, and which is made from nonbiological compounds and is manufactured and used in an essentially anhydrous state.